KR20120034103A - Surface decontamination of prefilled containers in secondary packaging - Google Patents

Abstract

Methods and systems for final sterilization and surface decontamination of prefilled containers containing sensitive agents, such as biotechnological drugs, that are sensitive to temperature or radiation and are not suitable for final sterilization by conventional methods using steam or gamma rays. It is described. Such methods and systems are particularly suitable for prefilled containers in secondary packaging. The method of the present invention includes exposing the prefilled container in the secondary packaging to variable beta rays for final sterilization, and also including means for reducing or preventing diffusion of vaporized hydrogen peroxide into the system. Final sterilization by exposure to adjustable vaporized hydrogen peroxide.

Description

Surface Decontamination of Prefilled Containers in Secondary Packaging}

The present invention relates to a method and system for final sterilization and / or surface decontamination of an outer surface of a prefilled container in a secondary packaging, wherein the prefilled container contains a medicament or a herbal product.

A prefilled container is a form of medical device that is filled at the time of assembly by the producer and supplied to the end user, generally a health care professional, or a patient in need of treatment in a sterile state.

Prefilled containers offer several advantages over traditional therapeutic packaging, which include ease of use, reduced risk of contamination, elimination of metering mistakes, increased drug delivery and reduced waste. Of the various forms of prefilled containers, prefilled syringes are the most common and most suitable for parenteral administration of therapeutic agents.

Various methods of sterilizing medical devices are known, but not all methods are available for syringes, especially prefilled syringes containing drug or protein solutions.

Steam sterilization is commonly used to sterilize medical devices and typically involves heating the device in a steam autoclave. However, the heat and pressure generated in the autoclave can adversely affect the integrity of the device, and more importantly, the drug filled into the device. Steam sterilization can damage the appearance of the product due to packaging degradation due to hot steam treatment. Moreover, high temperature processes (eg 120 ° C. to 132 ° C.) preclude the use of them in heat sensitive materials such as biotechnological drugs, in particular proteins or other biological solutions.

Radiation exposure is also commonly used to sterilize medical devices, in which the product is treated with ionizing radiation such as gamma rays. Radiation exposure can cause harmful damage to sensitive solutions and, in particular, produce large amounts of peroxides that not only destroy sensitive biomaterials such as proteins, but can also damage active ingredients in secondary reactions in aqueous solutions. In addition, sterile amounts of gamma rays brown the glass portions of the device and are susceptible to damage to elastic materials such as plungers and stoppers. Breaking the elastomer increases the stickiness of the part, impairing system function. Thus, radiation is not a suitable means to sterilize prefilled containers, such as syringes containing biotechnological drugs.

Cold sterilization is a term used collectively in sterilization methods that are carried out substantially below the steam process temperature. Attempts have been made to use ethylene oxide and hydrogen peroxide vapor as sterilizers for this treatment. However, treatment with sterile gas involves the risk of insufficient removal of oxidizing gas. As the gas diffuses into the product container, it affects the stability of the drug through chemical modifications, such as alkylation and oxidation, by the gas vapor.

Prefilled syringes are filled under sterile conditions, but are not packaged in secondary packaging in sterile environments, so the outer surface may be contaminated with microorganisms. Final sterilization of prefilled containers in secondary packaging is one way to provide devices with a low biofouling rate and low risk of contamination for end users to safely use the product. There is also a strong market demand for final antimicrobial-treated medical devices, such as prefilled syringes for use in intravitreal injection.

Because certain drugs, such as proteins, have sensitive properties, it is not possible to perform final sterilization and surface decontamination of containers filled with such drugs by conventional methods such as steam, irradiation or cold sterilization. Specifically, high temperatures are known to denature proteins, and gamma rays have been found to chemically modify biological solutions. Irradiation techniques, such as sterilization using gamma or beta rays, can lead to discoloration of the packaging material, affecting the long-term stability of therapeutic agents such as protein or peptide solutions. As discussed above, oxidizing gases are effective at killing contaminating bacteria but are harmful to biomolecules in sensitive therapeutic solution.

As proteins and biomolecules will be further developed for therapeutic use, final surface sterilization and surface decontamination methods that are not harmful to such drugs will increase further in the near future. Moreover, regulatory agencies may require higher levels of sterilization assurance, so pharmaceutical and biotechnology companies will find other ways to approach or meet the microbial purity requirements of the legislation without compromising the safety and efficacy of the drug. .

Herein, methods for final sterilization and surface decontamination treatment of prefilled containers, specifically methods for sterilizing prefilled containers containing sensitive solutions, such as drugs or biotherapeutics, in secondary packaging are described. In one embodiment, final sterilization is achieved by treating the prefilled container in the secondary packaging with adjustable vaporized hydrogen peroxide (VHP). The principle is to produce steam of hydrogen peroxide in an enclosed space and then to remove or inactivate the steam in a controlled manner. Prior to removal or inactivation, the VHP condenses on all surfaces to form a microbial bactericidal membrane that decontaminates the vessel surface.

It has been found that changing the parameters of antimicrobial treatment, such as temperature, humidity, treatment time, pressure, etc., creates a condition that prevents VHP from penetrating into the syringe. For example, at the end of the treatment a vacuum will be applied to reverse the diffusion direction and, if not stopped, to reduce the penetration of hydrogen peroxide through the rubber. In addition, a gas plasma treatment may be included after the vaporized hydrogen peroxide cycle to further decompose any hydrogen peroxide residues that may be present. Preventing or reducing the introduction of harmful concentrations of hydrogen peroxide into the protein solution in the prefilled syringe through the removal or inactivation of the vapor ensures that the long-term stability of the protein is not compromised. Of the commercially available primary packaging components, only a few packaging combinations have been found that provide the sealability of the system needed to prevent the entry of sterile gas into the chemical liquid sealed in a prefilled container.

The present disclosure also describes methods for final sanitization, sterilization or surface decontamination of prefilled containers in secondary packaging with variable electron beams (low-energy beta rays) as an alternative to sterile inspection or sterile secondary packaging operations.

In one embodiment, the use of low transmission depth radiation from a low-energy electron beam generator for fresh use to sterilize the surface of the secondary packaged drug container eliminates the need for sterile packaging. In another embodiment, the transmission depth of the electron beam radiation can be changed by adjusting the accelerator voltage of the radiation generator.

In general, the concepts provided by the present invention can be applied to any drug that requires or desires the absence of bioorganisms on the drug container surface. The methods and systems described herein decontaminate, or more preferably, sterilize, the outer surface of a primary packaged drug in a secondary package, thereby providing a high level of hygiene (eg, for use in a surgical operating room or intraocular injection). To improve product safety.

The above summary outlines some aspects of the invention. In other words, it is not intended to be exhaustive or to describe only essential / essential requirements.

The details of the invention are described with reference to the accompanying drawings. In the drawings, the leftmost digit of a reference number indicates the figure in which such reference first appears.
1 illustrates a prefilled container in a secondary package decontaminated on the surface according to the methods described in detail herein.
2 is a block diagram of an example system for surface decontamination of a prefilled vessel using vaporized hydrogen peroxide.
3 is a block diagram of an exemplary system for surface decontamination of prefilled containers using variable beta-ray irradiation.

The methods and systems described herein are sensitive to temperature or radiation or sensitive to traces of oxidizing materials, such as drugs that are not suitable for final sterilization by traditional methods including the use of vapors, gamma rays or beta rays or oxidizing gases or liquids. For sterilization and surface decontamination of prefilled containers containing sensitive solutions. The methods and systems described herein are particularly suitable for prefilled containers filled under sterile conditions and subjected to further processing such as product labeling and subsequent secondary packaging. The method of the present invention comprises exposing the prefilled container in the secondary packaging to variable beta-radiation for final sterilization and surface decontamination, and also providing means for reducing or preventing diffusion of vaporized hydrogen peroxide into the prefilled container. Including pre-filled vessels with adjustable vaporized hydrogen peroxide for final sterilization and surface decontamination. The method of the invention also includes an optional step of actively destroying the remaining peroxide molecules, such as with a gas plasma.

Justice

In describing and claiming the final sterilization and surface decontamination methods, the following terms will be used as defined below.

"Sterile" conditions are those that are free of bacterial or microbial contamination.

"Administration" refers to a method of administering a therapeutic agent to a subject or patient in need thereof, such as parenteral administration, intravenous administration or intraocular administration.

"Beta radiation" refers to a sterilization method using beta rays.

"Cold sterilization" refers to sterilization techniques using chemical sterilizers, gases or irradiation. The requirement of cold sterilization is that such techniques must be carried out at temperatures lower than those used for steam sterilization such as autoclaving.

As used herein, "container" refers to the storage of a medicament such as a vial, syringe, bag, bottle, or drug in solid or liquid form, or other biologic in solid or liquid form, such as a peptide, protein or recombinant biomass. It is intended to include other useful means. The container may be reusable or disposable and may be medical, veterinary or non-medical.

"Prefilled container" refers to a container, such as a syringe, that can be filled with a solution upon assembly and packaging and delivered for use by an end user, such as a healthcare professional or a patient in need of a therapeutic agent. The term also refers to a prefilled container integrated into the administration device.

"Instructions" or "instructions" includes any printed media, records, diagrams or any other expression medium that can be used to inform the usefulness of using the methods or systems of the present invention for its indicated purposes. The instructions or instructions may be provided together as part of the system, may be provided separately, or may be provided to the end user regardless of the process.

As used herein, "isolating" refers to practices in the production, filling, and packaging of a medicament, wherein a clean or sterile environment is separated from the non-sterile environment to inhibit or prevent the introduction, spread, or contamination of infectious agents such as microorganisms. Means that.

As used herein, a "medical device" is a device used to administer a medicinal therapeutic agent, whose production or sale must, in part, meet the requirements, such as safety requirements established by government authorities such as the Food and Drug Administration (FDA). do.

"Solution" refers to the contents of a container such as a vial or a fill syringe, and includes solutions of biotherapeutics, drugs, protein products, peptide products, biological products, imaging solutions, aqueous solutions. Preferably, the solution is a solution that is sensitive to temperature, oxidation or radiation due to its molecular composition.

"Secondary packaging" refers to the packaging surrounding a prefilled container, such as other suitable packaging, such as plastic wrapping, foil wrapping, paper wrapping or blister packs.

“Final antimicrobial surface treatment” refers to sanitizing or sterilizing an assembled container, eg, a syringe, filled with a solution and then wrapped in a secondary package. Final antimicrobial treatment, or sterilization, allows the secondary packaged prefilled container to be provided in a sterile external state at the time of use.

"Evaporated hydrogen peroxide" refers to hydrogen peroxide in the form of a vapor capable of producing a microbial bactericidal membrane on a surface, such as the surface of a container or package.

The terms "sterilization", "decontamination", "sanitary treatment" and "antimicrobial treatment" are used interchangeably herein.

By “sterile” herein is meant the complete absence of a microorganism, as defined by the probability of a non-sterile state or the level of sterility assurance (SAL). The required SAL for a given product is based on regulatory requirements. For example, the SAL required for a health care product corresponds to at least ^10-6 , ie less than 1 non-sterile product per million aseptically produced and final sterilized products each.

As used herein, “an embodiment” or “another embodiment” means that a specific feature, structure, operation, or characteristic described in connection with such embodiment is included in at least one embodiment of the present invention. Thus, when such phrases or expressions appear, they do not necessarily refer to the same embodiment. In addition, various specific features, structures, operations, or characteristics may be combined in any suitable manner in one or more embodiments.

Final sterilization and surface decontamination of prefilled containers

Final sterilization is the sterilization and / or decontamination process of the final packaged product. In contrast, sterile packaging processes require that individual product components be individually sterilized so that the final packaging is assembled in a sterile environment. Final sterilization of the product can more ensure the sterilization of the product than the sterile process. Final sterilization is also desirable and offers advantages in the market when using certain medical devices, such as using secondary packaged prefilled syringes for intraocular administration.

The present specification describes final sterilization methods suitable for prefilled containers containing sensitive products, such as biotechnological (biological) drug solutions, which may be used for steam, gamma irradiation or the like currently used in pharmaceutical production and assembly lines. Damage may occur in the use of traditional final sterilization processes such as cold sterilization processes. Although the description is directed to drugs such as heat or radiation sensitive drug solutions containing biomaterials such as peptides or proteins, those skilled in the art will be able to pre-fill any suitable drug that may be considered therapeutic, whether in solution or in solid form. It will be appreciated that it may be sealed or contained in a container. Thus, the prefilled container itself is not related to the drug.

The use of vaporized hydrogen peroxide in a prefilled container in the secondary packaging, treatment by controlled steam by certain post-treatment means, and exposure to variable beta radiation that can control the depth of penetration into the secondary packaging is prefilled. It has been found to be suitable for surface decontamination of containers and not detrimental to the stability or integrity of the prefilled container contents.

The methods and embodiments described herein are suitable for use in drug production and packaging outside the containment chamber or containment chamber. In addition, the methods described herein can be applied to different container formats or forms at a minimal cost to the production plant design. Also provided is a kit comprising a system for surface decontamination of a prefilled container in a secondary packaging, as well as instructions for practicing the methods and systems described herein.

In FIG. 1, the prefilled container 100 prefilled under sterile conditions is enclosed or packaged in a secondary package 104 and then decontaminated on the surface 102 by vaporized hydrogen peroxide or variable beta radiation described herein. do. Although FIG. 1 shows one exemplary prefilled container, those skilled in the art will understand that various containers other than syringes are also suitable. In addition, although the exemplary container shown in FIG. 1 is a syringe in a closed and assembled position, it should be understood that other variables may be included. For example, a prefilled container that is not closed by a stopper, plunger or other closure mechanism can be surface decontaminated inside the container.

In one embodiment, the prefilled container is a syringe. Other suitable prefilled containers are vials, bottles, bags and other medical devices that may contain sterile solutions or solutions that require sterilization.

In one embodiment, the syringe is filled with a drug, for example a drug in liquid, solution, powder or solid form. In another embodiment, the drug is a solution such as a drug solution or protein solution that is sensitive to exposure to oxidizing gases or ionizing energy such as high temperature, gamma rays or beta rays, such as those used in steam sterilization. In another embodiment, the drug is of the type that must be regenerated in liquid or solution prior to use as lyophilized, ie as a solid.

In another embodiment, the solution can be any drug that requires or desires to be sterilized on the drug container surface. In one particular embodiment, the drug is a protein solution, eg, ranibizumab (eg 6 mg / ml or 10 mg / ml) solution for intraocular administration.

In one embodiment, the container is filled with the solution under sterile conditions in an automatic or manual process. Thus, the contents of the container are sterile and are not affected by the surface decontamination methods described herein. "Filling" refers to filling a container, such as a solution, into the container in an appropriate amount, such as an appropriate volume or concentration. Appropriate amounts, volumes or concentrations will depend on the nature of the contents and intended use.

In one embodiment, the container is considered the primary packaging for the solution contained therein. In another embodiment, the prefilled container is packaged in a secondary package or a secondary package containing a prefilled container. Suitable secondary packaging includes lapping, eg, paper, plastic, foil wrapping and microbial impermeable blister packs.

In one embodiment, the prefilled container in the secondary package is subjected to a decontamination process such that the contents of the secondary package, specifically the surface of the prefilled container, are decontaminated and final sterilized. Thus, the prefilled container surface enclosed in the decontaminated secondary packaging by the method described herein is provided in an extremely hygienic or sterile environment such as an operating room and opened therein.

In one embodiment, final sterilization and surface decontamination of the prefilled vessel in the secondary packaging is performed by treating the surface of the prefilled vessel in the secondary packaging with vaporized hydrogen peroxide in the decontamination chamber and taking post-treatment measures. . Suitable decontamination chambers, such as autoclaves, have any means for reversibly closing the enclosed environment and can be any chamber equipped with means for manipulating pressure, temperature, air inlet and outlet within the chamber. . Additional elements of a suitable chamber include means capable of accommodating treatment with vaporized hydrogen peroxide, and means for reducing or preventing the entry of vaporized hydrogen peroxide into a prefilled vessel.

In another embodiment, the chamber is configured to receive a volume of a container requiring final sterilization. Thus, in large scale production and assembly lines, the chamber may be configured to accommodate a large amount of containers.

Treatment with vaporized hydrogen peroxide occurs by adding or releasing vaporized hydrogen peroxide in the decontamination chamber. In one embodiment, the vapor of hydrogen peroxide is adjustable, that is to say that certain post-treatment means are used to manipulate or control the action of vaporized hydrogen peroxide. In one embodiment, post-treatment means are used to direct (or reverse) the direction of vapor diffusion to prevent vapor from entering the prefilled vessel. In another embodiment, post-treatment means are used to destroy residual traces of peroxide.

In one embodiment, the post-treatment means comprises reducing or removing gas radicals formed by the action of vaporized hydrogen peroxide. In another embodiment, the post-treatment means comprises inactivating the action of vaporized hydrogen peroxide, eg, oxidative action.

In another embodiment, final sterilization and surface decontamination of the prefilled container in the secondary packaging is accomplished by irradiation of variable beta rays. In one embodiment, the surface of the prefilled container in the secondary packaging is decontaminated by adjusting the accelerator voltage of the irradiation generator to provide a sufficient amount of beta rays to penetrate the secondary packaging without penetrating the primary packaging.

In another embodiment, the accelerator voltage required to deliver an appropriate amount of beta rays to decontaminate the surface of the prefilled container depends on the thickness of the secondary packaging material. For example, in one embodiment, a suitable packaging material has a thickness of 0.05 mm or less. Such materials up to 0.05 mm in thickness are made of foil.

In another embodiment, shielding of the prefilled container contents is nearly complete by the primary packaging material, while combining the secondary and primary packaging components, the accelerator voltage, the irradiation plant design, and the processing speed to prefill the container in the secondary packaging. Perform surface decontamination.

In one embodiment, a suitable primary package is a syringe capable of shielding the radiation sensitive solution contained therein. Shielding protection is provided by the thickness of the vessel wall or the material component of the vessel. The shielding protection effect can be determined by adjusting the accelerator voltage, ie by the penetration depth of the beta rays emitted onto the prefilled vessel. In addition, the shielding protection effect can be determined by measuring the absorbed dose, for example, with a dosimeter.

It is understood by those skilled in the art that the prefilled container is assembled under aseptic conditions such that the contents of the container are sterile. While the contents of the container are sterile, the surface of the container may be contaminated during subsequent packaging and product labeling when using standard drug packaging protocols. For surface decontamination of prefilled containers, the sterilization methods of the present invention can be used for standard production and packaging of drugs in or outside the containment chamber.

In one embodiment, prefilled containers, prefilled under aseptic conditions by manual or automated processes, labeled and packaged in secondary packaging, are sent to an electron beam tunnel for final sterilization and surface decontamination of the final packaged product. In one embodiment, the prefilled container in the secondary packaging is introduced into the electron beam tunnel through the inlet by a manual or automatic process or a combination thereof and during all or part of the time being transported through the electron beam tunnel to the outlet. The surface of the prefilled container in it is exposed to low-energy beta rays. In another embodiment, the prefilled container in the secondary packaging has its surface exposed to low-energy beta rays in a stationary state for all or part of the time. In another embodiment, the electron beam is oscillated by, for example, applying a magnetic field such that the entire surface of the irradiated object is scanned by the electron beam. In another embodiment, the irradiated object is passed under the scanning electron beam by means of a transport mechanism, such as a moving conveyor. In another embodiment, the electron beam processing chamber is open but shielded from the environment by a tortuous path that allows objects to enter and exit the chamber.

Final Sterilization of Prefilled Containers with Vaporized Hydrogen Peroxide ( VHP )

In one embodiment, final sterilization of the prefilled container in the secondary packaging is carried out by antimicrobial treatment with hydrogen peroxide vaporized in the chamber, also referred to as "cold sterilization".

Various steps or tasks involved in sterilization and surface decontamination processes can be performed automatically under the control of a system manager such as a microprocessor. Alternatively, the work may be performed individually manually. In addition, the work can be carried out in combination with automatic and manual processes.

In one embodiment, the prefilled container is filled under sterile conditions and then enclosed in a secondary package. In another embodiment, the prefilled container is labeled with product information, such as product name, instructions for use, etc., before placing in secondary packaging.

In one embodiment, the prefilled container in the secondary packaging is provided manually or automatically in the decontamination chamber and then secured therein.

Suitable decontamination chambers, such as autoclaves, are equipped with means for reversibly sealing the enclosed environment, and any vessel equipped with means for manipulating pressure, temperature, air inlet and outlet within the chamber. It is possible. Additional elements of a suitable chamber include means for accommodating treatment by VHP and post-treatment means for reducing or preventing entry of VHP into a prefilled container. Another additional element of the chamber is a means of destroying residual traces of peroxide.

In one embodiment, hydrogen peroxide vapor is introduced into the chamber and generated or released in the chamber for a time sufficient to decontaminate or treat the surface of the prefilled container in the secondary packaging. In another embodiment, the treatment with vaporized hydrogen peroxide is carried out at lower temperatures than those used for steam sterilization.

Hydrogen peroxide in liquid form has long been recognized as a fungicide. U.S. Patent No. 4,512,951 to Kuoubek describes a sterilization method using liquid hydrogen peroxide, which vaporizes an aqueous solution of hydrogen peroxide and passes the resulting hydrogen peroxide-water vapor mixture into a degassed sterilization chamber to be sterilized. Vapor in condensation upon contact with the object to form a liquid hydrogen peroxide layer on the object. The object to be sterilized must be kept at a temperature below its dew point to ensure condensation of the hydrogen peroxide-water mixture, but the overall chamber temperature must be high enough so that incoming steam does not condense before reaching the object. After sterilization for a suitable time, the condensate is re-evaporated by passing filtered, preferably heated air over the object surface. Sterilization using gaseous hydrogen peroxide is described in US Pat. No. 4,169,123 to Moore et al. And US Pat. No. 4,169,124 to Forstrom et al. The methods described in these two patents include surrounding the product to be sterilized with vapor phase hydrogen peroxide and maintaining the contact between the product and the sterilant at a temperature below 80 ° C. until sterilization is achieved. The lowest temperature disclosed in the Moor or Postrom patent is 20 ° C.

In sensitive solutions, such as protein solutions, infiltration of vaporized hydrogen peroxide into a prefilled vessel has been found to be detrimental to the molecular integrity of the solution because hydrogen peroxide vapor entering the vessel causes chemical changes in the solution such as oxidation.

It has been found that post treatment or post application measures can be taken to reduce or prevent the negative effects of VHP on sensitive solutions and to preserve the integrity of the sensitive solution in the prefilled container, ie the therapeutic efficacy. The post-application means is preferably a means for removing the vaporized hydrogen peroxide or inactivating the hydrogen peroxide vapor to inactivate the oxidation of hydrogen peroxide.

In one embodiment, the penetration of the VHP into the prefilled vessel is prevented by applying a vacuum in the chamber at the end of the antimicrobial treatment to reverse the diffusion direction of the hydrogen peroxide vapor. By reversing the direction of the vapor flow, hydrogen peroxide vapor is prevented from entering the prefilled vessel, thus maintaining the integrity of the sensitive solution in the vessel while decontaminating the surface of the vessel.

In another embodiment, hydrogen peroxide is inactivated to such an extent that the solution contained in the prefilled vessel cannot be chemically changed. In another embodiment, the post-treatment means comprises neutralizing the oxidizing capacity of the hydrogen peroxide vapor. In another embodiment, the hydrogen peroxide vapor is inactivated by irradiating the vessel with ultraviolet light after sufficient time exposure of the prefilled vessel to VHP after treatment. The appropriate deactivator according to example, such as a chemical or a gas plasma, may be used to inactivate the VHP after exposing the surface of the prefilled container to the VHP for a sufficient time.

As a final sterilization process, prefilled containers in secondary packaging can be withdrawn from the chamber, which is suitable for use by the end user.

In one embodiment, the sterilization process can be performed by an automated system. For example, FIG. 2 shows a block diagram of a system 200 for decontaminating the surface of a prefilled container in a secondary package. System 200 includes an enclosed chamber 202 and a control device 204 coupled directly or indirectly thereto.

In one embodiment, the closed chamber 202 may be any suitable decontamination chamber. For example, chamber 202 includes an autoclave having the ability to reversibly close a closed environment. Chamber 202 is also equipped with a mechanism capable of manipulating the inlet and outlet of temperature, pressure and air in chamber 202.

The control device 204 instructs the chamber 202 to perform a task relating to sterilizing the prefilled container 100 (eg, as shown in FIG. 1) in a pre-set, automated manner. Provided in the form. The control device 204 may transmit a signal to the chamber 202 to induce the chamber 202 (or related components) to physically allow vaporized hydrogen peroxide to contact the surface of the prefilled container in the secondary packaging. Can be.

For example, in one embodiment, the control device 204 can signal a valve (not shown) connected with a reservoir for transporting vaporized hydrogen peroxide into the chamber. The control device 204 measures a preset residence time such that vaporized hydrogen peroxide remains in contact with the prefilled vessel surface. After a preset dwell time, the control device 204 signals the chamber 202 (or associated device) to enable a means to reduce the presence of vaporized hydrogen peroxide in the chamber so that the vaporized hydrogen peroxide is decontaminated. Prevents diffusion into the filled container.

For example, after surface decontamination, the control device 204 may signal a vacuum means (not shown) to remove these vapors from the chamber by reversing the direction of the hydrogen peroxide vapor and directing it out of the chamber 202. . Another suitable control mechanism for regulating hydrogen peroxide vapor is to introduce neutralizing or inactivating agents, such as chemicals into the chamber 202 to inactivate the vapors when in contact with the hydrogen peroxide vapors, thus detrimental to the solution inside the prefilled vessel. Includes a mechanism to prevent this from happening.

Mention may be made of sufficient processing time to final sterilize the prefilled container. In one embodiment, a treatment time sufficient to sufficiently decontaminate the vessel surface or residence time in the chamber of vaporized hydrogen peroxide can be determined by routine validation. For example, a vessel treated with evaporated hydrogen peroxide is compared to a control and incubated in a bacterial growth medium with a standard test protocol, such as a subject suspected of contamination, and generally biomarkers are used to determine whether the bacteria have grown. Test methods can be used to check for bacterial contamination. By plotting the treatment time for the presence of bacterial growth, one can easily determine the treatment time to achieve decontamination, i.e., absence of bacterial growth. Validation techniques apply both where the final sterilization is carried out with evaporated hydrogen peroxide as described above or by beta rays as described below.

In one embodiment, the control device 204 is automated, operating in accordance with code executing the processor. Mounting the control device will be within the skill level of those skilled in the art. For example, the control device may be a personal computer or a microprocessor or may be any other suitable device capable of executing code programmed to signal a device associated with physically performing a sterilization process.

It will be appreciated that the various steps or operations involved in the final sterilization and surface decontamination process may be performed automatically under the control of the control device as described above. Alternatively, the tasks can be separated into manual tasks and performed separately. In addition, the work can be performed in combination with automatic and manual processes.

Variability  Final sterilization of prefilled containers by beta ray irradiation

In one embodiment, the final sterilization of the prefilled container in the secondary packaging is decontamination treatment in a chamber equipped with one or more electron beam generators that can be adjusted to generate an appropriate amount of beta rays onto the surface of the prefilled container. Is carried out.

The various steps or tasks involved in the final sterilization and surface decontamination process can be performed automatically under the control of a system manager such as a microprocessor. Alternatively, the tasks can be separated into manual tasks and performed separately. In addition, the work can be performed in combination with automatic and manual processes.

In one embodiment, the prefilled container is filled under sterile conditions and then enclosed in a secondary package. In another embodiment, the prefilled container is labeled with product information, such as product name, label, instructions for use, etc., prior to being contained in the secondary packaging.

In one embodiment, the prefilled container in the secondary packaging is provided manually or automatically in a decontamination chamber having an inlet side and an outlet side. In another embodiment, the decontamination chamber is an electron beam tunnel. In another embodiment, the prefilled vessel moves mechanically on a moving mechanism, such as a conveyor, from the inlet to the outlet through the tunnel. Thus, as the prefilled vessel moves through the chamber, the prefilled vessel surface is exposed to beta rays.

In another embodiment, the electron beam is oscillated, for example by application of a magnetic field, such that the entire surface of the object is scanned by the electron beam. In another embodiment, the object passes under the scanning electron beam by a transport mechanism such as a moving conveyor.

In one embodiment, the prefilled container surface in the secondary packaging is decontaminated for exposure times of low permeation beta rays of less than 1 second, preferably less than 0.5 seconds. Thus, the treatment time with variable beta rays described herein is considerably shorter than when using gamma rays that require several hours or more of surface treatment time for sufficient decontamination and sterilization.

In another embodiment, the electron beam tunnel consists of an electron beam generator and the energy voltage generated is variable.

In another embodiment, the prefilled container in the secondary packaging is transported or moved around in such a way that the entire surface of the container is exposed to beta rays emitted within the tunnel.

Primary packaging containers for sterile drugs are often about 30 times thicker than secondary packaging materials. In one embodiment, the wall thickness of the primary packaging material is at least 20 times thicker than the thickness of the secondary packaging material, such that the amount absorbed by the contents in the prefilled container is less than 0.1 kGy.

While the contents of the vessel are essentially shielded by the primary packaging material, in search of a combination of packaging components, accelerator voltage, irradiation plant design and processing speed that enable surface decontamination or surface sterilization of the prefilled vessel in the secondary packaging. It turns out that you can. Thus, beta rays do not affect sensitive biomolecules, such as biotechnological drug solutions inside the primary packaging material.

In one embodiment, beta-ray irradiation to a prefilled container is carried out using known beta-ray radiating devices, such as low voltage generators or particle accelerators, in an amount useful to provide effective sterilization without degrading the container or its contents. In this case, the radiation dose may vary depending on the thickness of the secondary pavement.

In one embodiment, the minimum sterilization amount (MSD) of the beta rays is the amount necessary to deliver the SAL required for the product. In one embodiment, the sterile amount is measured in Gray (Gy) or Rad (radiation absorbed dose). In another embodiment, the absorbed dose is measured with a dosimeter, preferably a film dosimeter, calorimeter or cerium dosimeter.

In another embodiment, the radiation dose depends on the presence of the secondary packaging and the thickness of the secondary packaging. In a typical prefilled container, beta radiation is preferably provided at a dose of 25 kGy to the surface of the prefilled container.

In one embodiment, the particle accelerator generates beta particle acceleration through the vacuum tube. In one embodiment, the acceleration is by magnetic field or electrostatic charge or by energy transfer from high frequency electromagnetic waves.

 As a final stage of the final sterilization process, the prefilled container in the secondary packaging exits the tunnel at the exit with the surface decontaminated and is suitable for use by the end user. Since the surface decontamination treatment time is as short as about 1 second, surface decontamination of prefilled containers in secondary packaging is harmful to container contents, requires a fairly long exposure time for decontamination, and further along the production line. It has several advantages over sterilization methods that use gamma radiation, which requires shielding protection and causes discoloration of packaging components. In addition, sterilization techniques involving gamma rays cause significant bottlenecks in production assembly lines, which can be eliminated by surface decontamination using variable beta rays in the electron beam tunnel.

In one embodiment, as shown in FIG. 3, a system 300 for surface-decontamination of a prefilled container in a secondary packaging is equipped with one or more variable electron beam generators shown as voltage generators 304. Electron beam tunnel 302. In another embodiment, one or more variable electron beam generators 304 of the system are configured to variably generate low-energy beta rays. Alternatively, the electron beam is oscillated so that the electron beam impinges on the larger area of the prefilled vessel and increases the exposed surface of the vessel.

In another embodiment, the one or more generators 304 apply an accelerator voltage to generate an amount of beta rays sufficient to decontaminate the surface of the prefilled vessel, wherein the sufficient amount of beta rays is the thickness of the secondary packaging and the prefilled vessel. Depends on its thickness. Thus, beta rays penetrate the secondary packaging, while the thickness of the prefilled container shields the contents from beta rays.

Mention may be made of sufficient processing time to final sterilize the prefilled container. In one embodiment, sufficient treatment time or time of low-energy beta radiation in the tunnel to sufficiently decontaminate the container surface can be determined by routine validation. For example, a container treated with beta rays may be compared with a control, and standard test protocols such as incubating suspected contamination in bacterial growth medium and then testing for bacterial growth may be used to determine bacterial contamination. Can be checked By plotting the treatment time for the presence of bacterial growth, one can easily determine the treatment time to achieve decontamination, i.e., absence of bacterial growth. Validation techniques apply both where the final sterilization is carried out by beta rays as described above or by vaporized hydrogen peroxide as described above.

Reference is now made to the examples below. These examples are given for purposes of illustration only, and in no sense should the present invention be construed as being limited to these embodiments, but as including all modifications of the invention which are apparent from the teachings provided herein. do.

Example  One

In the experiments below, the prefilled syringes were sterilized with evaporated hydrogen peroxide in the chamber and either passed through the VHP sterilization process or twice through the VHP sterilization process (indicated by 2x in the table below). Syringes containing protein solutions treated with VHP were compared to control syringes treated with VHP to determine if the integrity of the protein present in the solution was maintained.

To test for protein degradation after treatment with VHP, the composition described in US Pat. No. 7,060,269 was used.

About 10 ml of the solution was filtered through a 0.22 μm syringe filter (Millex GV filter, manufactured by Millipore, Billerica, MA USA). 0.5 ml each was filled into syringes in a sterile laboratory for hydrogen peroxide treatment.

Analysis after treatment with VHP showed the following protein content visualized according to HPLC analysis: by-products and degradation products by HPLC (IEC) and by-products and degradation products by HPLC (SEC).

The result was to meet the requirements. There was no difference between the results of untreated syringes and syringes treated with hydrogen peroxide. Assays were performed at different time points after treatment, such as one month, three months and six months after treatment with VHP, or after a storage period of prefilled container product. Assays can be performed to determine the continued stability of the protein solution and include HPLC testing for the presence of byproducts using standard HPLC experimental protocols. Assays can also be carried out by the presence of physical changes, for example H in solution by fluorescence testing using an over-the-counter commercial kit with a device with fluorescence detection. Measuring the concentration of ₂ O ₂ .

Example  2

The following experiment was conducted to determine the effect of surface decontamination using beta rays. A commercially available electron beam tunnel equipped with a KeVAC accelerator from Linac Technologies, Orsay, France for external decontamination of the vessel was used to investigate the penetration depth of the electron beam among different materials. For example, permeation was measured in polyethylene bags having a foil thickness of 50 μm, aluminum bags having a foil thickness of 0.1 mm, and glass slides having a thickness of 1 mm.

To increase the sensitivity of the study, samples were passed through the tunnel several times. The amount of radiation absorbed was recorded using a Far West 60 film dosimeter (commercially available from Far West Technologies, Santa Barbara, Calif., USA).

Feasibility studies have shown that surface sterilization can be obtained by treatment with a setting of an unoptimized electron beam decontamination tunnel when the product is packaged into a plastic bag (> = 25 kGy). Even after five passes through the electron beam treatment tunnel, the dose absorbed in the packaging material (behind the 1 mm thick glass wall) was much lower than the quantitative limit of 1 kGy for the dosimeter used.

In addition, the oxidative stress on a 0.5% polysorbate 20 solution in a prefilled glass syringe (1 mL elongated form, ISO) was investigated by measuring peroxides according to standard protocols. The total amount of peroxide was measured by ferrous oxide oxidation (FOX) test, according to standard protocols.

It could be observed that the electron beam treatment had no significant effect on the content of peroxides in the solution enclosed in the glass syringe. Thus, beta-ray irradiation has proven to be safe for solutions in prefilled containers.

In addition, the oxidative stress applied to the protein solution in prefilled glass vials was examined by measuring degradation products according to standard protocols.

The composition described in US Pat. No. 7,060,269 was tested for protein degradation after electron beam irradiation treatment. About 0.3 ml of the solution was filtered through a 0.22 μm filter and pre-sterilized glass vials were filled under sterile conditions, sealed with sterile rubber stoppers under sterile conditions and then fixed with an aluminum crimp cap.

The vessel was passed through the electron beam tunnel set equal to the other experiments mentioned above. After irradiation with an electron beam, the protein content was measured and visualized by HPLC analysis for byproducts and HPLC (IEC) for degradation products, as performed in Example 1.

As shown in Table 4, there was no difference between the results of electron beam sterilized vials after one, three or five passes of the untreated syringe and electron beam sanitation process. Thus, the variable beta-ray irradiation described herein has proven safe for solutions in prefilled containers.

The above embodiments are in any sense merely illustrative of the invention and should not be taken as limiting thereof. The scope of the invention should therefore be defined by the appended claims rather than the foregoing description. All changes which come within the meaning and range of equivalency of the claimed invention are to be considered within their scope.

Claims (20)

Vaporized hydrogen peroxide is added to the surface of the prefilled container in the secondary packaging;
Allow vaporized hydrogen peroxide to contact the prefilled vessel surface for a time sufficient to decontaminate the prefilled vessel surface;
By means of decontamination means to reduce the presence of vaporized hydrogen peroxide to prevent the diffusion of vaporized hydrogen peroxide into the prefilled vessel.
A method of decontaminating a surface of a prefilled container in a secondary package, comprising. The method of claim 1, wherein the prefilled container is a syringe containing a drug sensitive to sterilization by gamma rays, sterilization by exposure to steam and sterilization by exposure to gasifiers and gases. The method of claim 1 or 2, wherein the prefilled container is a syringe containing a therapeutically effective amount of ranibizumab. The method according to claim 1, wherein a time sufficient to decontaminate the surface of the prefilled container is determined by verifying the treatment time and comparing with the control standard. The method according to any one of claims 1 to 4, wherein after decontamination means is used to reverse the diffusion direction of vaporized hydrogen peroxide using a vacuum after the treatment with vaporized hydrogen peroxide, and into the vessel pre-filled with vaporized hydrogen peroxide. Preventing the penetration. The method according to any one of claims 1 to 4, wherein the means after decontamination comprises applying ultraviolet light after the treatment with vaporized hydrogen peroxide to inactivate the oxidation of the hydrogen peroxide vapor. The method according to any one of claims 1 to 4, wherein the decontamination means comprises gas plasma treatment. One or more tunable electrons in the prefilled vessel in the secondary packaging can variably generate low-energy beta rays and can oscillate an electron beam such that a larger area of the prefilled vessel is exposed to beta rays during the decontamination process. Providing an electron beam tunnel equipped with a beam generator;
Applying an accelerator voltage of one or more tunable electron beam generators to generate an amount of beta rays sufficient to decontaminate the surface of the prefilled vessel, wherein a sufficient amount of beta rays is determined by the thickness of the prefilled vessel. Shielding from beta rays while varying the thickness of the secondary packaging and the thickness of the prefilled container so that the beta rays penetrate the secondary packaging,
Method for surface decontamination of prefilled containers in secondary packaging. The method of claim 8, wherein the wall thickness of the primary packaging material is at least 20 times thicker than the thickness of the secondary packaging material to reduce the dose absorbed by the product in the container to less than 0.1 kGy. The solution or solid according to claim 8 or 9, wherein the prefilled container is sensitive to sterilization by gamma rays, sterilization by exposure to steam and sterilization by exposure to gasifiers, gases or peroxide forming substances. Method of filling vials. The solution according to any one of claims 8 to 10, wherein the prefilled container is a solution that is sensitive to sterilization by gamma rays, sterilization by exposure to steam and sterilization by gasifiers, gases or peroxide forming substances. The method is a filled syringe. 12. The method of any one of claims 8-11, wherein the prefilled container is a syringe containing a therapeutically effective amount of ranibizumab. The method according to any one of claims 8 to 12, wherein the penetration depth is measured by dosimetry. The method of claim 8, wherein sufficient energy to decontaminate the surface of the prefilled vessel provides a beta dose of at least about 25 kGy to the vessel surface. 15. The method of any one of claims 8-14, wherein sufficient energy to decontaminate the surface of the prefilled vessel provides a beta dose that imparts a ^10-6 sterilization assurance level to the exterior of the vessel surface. . A closed chamber; And
A control device coupled to the chamber, which can automatically contact (i) vaporized hydrogen peroxide with the surface of the prefilled vessel in the secondary packaging, and (ii) vaporize hydrogen peroxide for the precharged vessel surface for a predetermined time. And (iii) a control device configured to operate post-decontamination means to reduce the presence of vaporized hydrogen peroxide in the chamber to prevent diffusion of vaporized hydrogen peroxide into the prefilled vessel.
And a system for decontaminating the surface of the prefilled container in the secondary packaging. An electron beam tunnel equipped with one or more variable electron beam generators, wherein the variable electron beam generator (i) variably generates low-energy beta rays, and (ii) a larger area of the prefilled vessel is exposed to beta rays Oscillates the electron beam as much as possible, and (iii) applies an accelerator voltage to generate a sufficient amount of beta rays to decontaminate the surface of the prefilled vessel, wherein the sufficient amount of beta rays is determined by the thickness of the prefilled vessel. A system for decontaminating the surface of a prefilled container in a secondary package, wherein the contents of the secondary package depend on the thickness of the secondary package and the thickness of the prefilled container such that the contents of the interior are shielded from the beta rays while the beta rays penetrate the secondary package. (i) adding vaporized hydrogen peroxide to contact the surface of the prefilled vessel in the secondary packaging, and (ii) keeping the vaporized hydrogen peroxide in contact with the prefilled vessel surface for a predetermined time in a closed chamber, ( iii) in a closed chamber, including instructions to use a closed chamber to operate post-contamination means to reduce the presence of vaporized hydrogen peroxide in the chamber to prevent vaporized hydrogen peroxide from diffusing into the prefilled vessel. Kit for decontaminating the surface of prefilled containers in secondary packaging. (i) variably produces low-energy beta rays in contact with the surface of the prefilled vessel, and (ii) generates a sufficient amount of beta rays to decontaminate the surface of the prefilled vessel, with a sufficient amount of beta rays Prefilled in the secondary packaging, including an indication that the thickness of the prefilled vessel will depend on the thickness of the secondary packaging and the thickness of the prefilled vessel so that the beta rays penetrate the secondary packaging while shielding the contents therein from the beta rays. Kit for decontaminating the surface of the container. 19. The system or kit according to claim 16 or 18, wherein the decontamination means comprises gas plasma treatment.

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